Project Summary Glutamate transporter EAAT2 plays a critical role in the homeostatic regulation of extracellular glutamate levels. EAAT2 also plays an essential role in cognitive memory functions. However, loss of EAAT2 protein and function are commonly found in Alzheimer?s Disease (AD) patients and are an early event in disease pathology. We recently discovered that restoration of EAAT2 protein function by a novel brain-penetrant small molecule, which we previously identified as capable of increasing EAAT2 expression through translational activation, significantly improved cognitive functions and restored synaptic integrity in an APP mouse model of AD. We have actively optimized this compound series and identified a number of potent and orally bioavailable compounds. In this application, we seek support to move the project forward from optimized compounds to a clinical candidate. In Year 1, we will focus on identifying the lead molecule from a group of ten fully optimized compounds through a series of in vitro and in vivo efficacy, selectivity, and safety evaluations. In Years 2-3, we will focus on evaluation of the lead molecule in two AD models, APPSw,Ind mice and rTg(tauP301L)4510 mice, and identify the compound as the clinical candidate.